The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Rh Prager - One of the best experts on this subject based on the ideXlab platform.
-
3-amino-2-(4-chlorophenyl)-nitropropane is a new GABAB receptor agonist, more active peripherally.
European Journal of Pharmacology, 1993Co-Authors: David I B Kerr, Jennifer Ong, John Abbenante, David J. Doolette, Rh PragerAbstract:Abstract The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABAB receptors. N-BAC was less potent than baclofen as a GABAB receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC50s for baclofen = 4.1 ± 1.3 μM; N-BAC = 9.2 ± 0.3 μM) and vas deferens (IC50s for baclofen = 30 μM; N-BAC = 100 μM), competitively antagonished by phaclofen, 2-hydroxySaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA2 values for CGP 35348 with baclofen (4.7 ± 0.2) and N-BAC (4.6 ± 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABAB receptor agonist, N-BAC, is thus more active at peripheral than central GABAB receptors.
Lorenzo Leggio - One of the best experts on this subject based on the ideXlab platform.
-
a deeper insight into how gaba b receptor agonism via baclofen may affect alcohol seeking and consumption lessons learned from a human laboratory investigation
Molecular Psychiatry, 2021Co-Authors: Mehdi Farokhnia, Sara L Deschaine, Armin Sadighi, Lisa A Farinelli, Mary R Lee, Fatemeh Akhlaghi, Lorenzo LeggioAbstract:Previous studies suggest that GABA-B receptor agonism may represent an effective pharmacological approach to treat addictive disorders. Baclofen is a selective GABA-B receptor agonist which has been investigated as a potential treatment for alcohol use disorder. However, research is needed to understand the biobehavioral mechanisms underlying baclofen’s effect on alcohol use. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals were randomized to receive baclofen (30 mg/d) or placebo for a week, and then participated in a laboratory experiment consisting of three procedures: alcohol cue-reactivity, priming, and self-administration. During the experiment, craving and other subjective responses to alcohol were assessed, and blood samples were collected for pharmacokinetic measurements. The effects of baclofen on the relationships between different alcohol-related laboratory parameters were investigated. Baclofen pharmacokinetic parameters and their correlations with behavioral measures were also examined. Results showed that baclofen disrupted the link between alcohol priming and self-administration, as indicated by significant interaction effects between drug condition (baclofen vs. placebo) and some of the priming variables (alcohol craving: F3,9 = 6.03, p = 0.01; alcohol sedation: F3,6 = 7.16, p = 0.01) on the total amount of alcohol self-administered. Considerable interindividual variability in baclofen pharmacokinetic parameters was observed. Maximum plasma concentrations of baclofen negatively correlated with cue-induced alcohol craving (r = −0.57, p = 0.03) and priming-induced ratings of ‘like more’ (r = −0.59, p = 0.02). In conclusion, baclofen may work by dissociating the link between an initial drink (priming) and subsequent alcohol consumption (self-administration). Considerable pharmacokinetic variability is an important factor to take into account when employing baclofen as a treatment for alcohol use disorder.
-
biobehavioral effects of baclofen in anxious alcohol dependent individuals a randomized double blind placebo controlled laboratory study
Translational Psychiatry, 2017Co-Authors: Mehdi Farokhnia, Lisa A Farinelli, Mary R Lee, Melanie L Schwandt, Jared W Bollinger, J P Amodio, L Sewell, T A Lionetti, D E Spero, Lorenzo LeggioAbstract:Baclofen has been suggested as a potential pharmacotherapy for alcohol use disorder, but the clinical data are conflicting. Here we investigated the biobehavioral effects of baclofen in a sample of anxious alcohol-dependent individuals. This was a randomized, double-blind, placebo-controlled, human laboratory study in non-treatment seeking alcohol-dependent individuals with high trait anxiety (N=34). Participants received baclofen (30 mg per day) or placebo for at least 8 days, then performed an experimental session consisting of alcohol cue-reactivity followed by alcohol administration procedure (alcohol priming, then alcohol self-administration). Total amount of alcohol self-administered was the primary outcome; alcohol craving, subjective/physiological responses and mood/anxiety symptoms were also evaluated. There was no significant medication effect on the total amount of alcohol consumed during the alcohol self-administration (P=0.76). Baclofen blunted the positive association between maximum breath alcohol concentration during priming and the amount of alcohol consumption (significant interaction, P=0.03). Ratings of feeling intoxicated were significantly higher in the baclofen group after consuming the priming drink (P=0.006). During the self-administration session, baclofen significantly increased ratings of feeling high (P=0.01) and intoxicated (P=0.01). A significant reduction in heart rate (P<0.001) and a trend-level increase in diastolic blood pressure (P=0.06) were also detected in the baclofen group during the alcohol laboratory session. In conclusion, baclofen was shown to affect subjective and physiological responses to alcohol drinking in anxious alcohol-dependent individuals. These results do not support an anti-craving or anti-reinforcing effect of baclofen, but rather suggest that baclofen may act as a substitution medication for alcohol use disorder.
Richard J Bodnar - One of the best experts on this subject based on the ideXlab platform.
-
gaba a and gaba b receptors mediate feeding elicited by the gaba b agonist baclofen in the ventral tegmental area and nucleus accumbens shell in rats reciprocal and regional interactions
Brain Research, 2010Co-Authors: Patricia Miner, Yaffa Borkuhova, Lyudmila Shimonova, Arthur Khaimov, Richard J BodnarAbstract:Abstract Food intake is significantly increased following administration of GABA-B and GABA-A agonists into the nucleus accumbens (NAC) shell and ventral tegmental area (VTA) with receptor-selective antagonist pretreatment capable of blocking these responses within sites. Regional interactions in feeding studies have been evaluated by administering an antagonist in one site of interest prior to administration of the feeding-active agonist in a second site of interest and have identified important relationships, particularly for opioid–opioid interactions. To evaluate whether regional and reciprocal VTA and NAC shell interactions occur for GABA-mediated feeding, the present study examined whether feeding elicited by the GABA-B agonist, baclofen, microinjected into the NAC shell was dose-dependently blocked by pretreatment with either the GABA-B antagonist, Saclofen, or the GABA-A antagonist, bicuculline, into the VTA, and then whether VTA baclofen-induced feeding was dose-dependently blocked by NAC shell pretreatment of either Saclofen or bicuculline in rats. Rats were stereotaxically implanted with bilateral pairs of cannulae aimed at the VTA and NAC shell and were assessed for food intake following vehicle and baclofen (200 ng) in each site. Baclofen produced similar magnitudes of increased food intake following VTA and NAC shell treatment. Baclofen administration in the VTA and NAC shell was preceded 20 min earlier with administration of bicuculline (0, 7.5, 75, 150, 300 ng) or Saclofen (0, 0.5, 1.5, 3, 5 μg) into the other site with intake measured 1, 2 and 4 h after agonist treatment. VTA Saclofen dose-dependently and significantly blocked feeding elicited by NAC shell baclofen. Correspondingly, NAC shell Saclofen dose-dependently and significantly blocked feeding elicited by VTA baclofen, indicating a robust and bidirectional GABA-B/GABA-B receptor interaction between sites. Whereas VTA bicuculline significantly blocked the increased feeding elicited by NAC shell baclofen, NAC shell bicuculline reduced but did not block feeding elicited by VTA baclofen, indicating a unidirectional interaction GABA-B/GABA-A receptor interaction between sites. Unlike within-site receptor specificity governing the ability of GABA agonist mediation of food intake, the present study demonstrates that GABA, like opioids, employs a distributed brain network in mediating its ingestive effects, and that under certain circumstances, uses multiple receptor subtypes to underlie its regional effects.
-
lack of intersite gaba receptor subtype antagonist effects upon μ opioid receptor agonist induced feeding elicited from either the ventral tegmental area or nucleus accumbens shell in rats
Physiology & Behavior, 2003Co-Authors: Tsippa F Ackerman, Nicole Lamonte, Richard J BodnarAbstract:Abstract Pretreatment with the GABAA receptor antagonist, bicuculline or the GABAB receptor antagonist, Saclofen, into the nucleus accumbens (Nacc) shell, respectively, potentiates and reduces feeding elicited by the μ opioid agonist, [ d -Ala2, Nme4, Gly-ol5]-enkephalin (DAMGO), administered into the same site. DAMGO-induced feeding elicited from the ventral tegmental area (VTA) region is significantly reduced by pretreatment with Saclofen into the same site indicating local GABA mediation of opioid-induced feeding in each site. Given the neuroanatomical and functional connections between the two sites, the present study evaluated the dose-dependent actions of bicuculline and Saclofen pretreatment in one site upon DAMGO-induced feeding elicited from the second site. Pretreatment of either bicuculline (7.5–75 ng) or Saclofen (1.5–10 μg) into the Nacc shell failed to alter the time course or magnitude of DAMGO-induced feeding elicited from the VTA region. DAMGO-induced feeding elicited from the Nacc shell was unaffected by VTA region pretreatment with either bicuculline (7.5–75 ng) or Saclofen (1.5–5 μg). A higher (10 μg) Saclofen dose prevented significant DAMGO-induced feeding after 1 and 4 h. Thus, although GABA receptor subtype antagonists are capable of differentially modulating DAMGO-induced feeding when both drugs are applied locally in either the VTA region or the Nacc shell, it appears that any effects between the VTA region and the Nacc shell in modulating DAMGO-induced feeding do not depend upon a GABAergic synapse in the other site.
-
alterations in food intake elicited by gaba and opioid agonists and antagonists administered into the ventral tegmental area region of rats
Physiology & Behavior, 2002Co-Authors: Joyce A Echo, Nicole Lamonte, Tsippa F Ackerman, Richard J BodnarAbstract:Food intake is significantly increased following administration of mu-selective opioid agonists into the ventral tegmental area (VTA) region acting through multiple local opioid receptor subtypes. Since GABA receptor agonists in the VTA region are capable of eliciting feeding, the present study investigated whether feeding elicited by the mu-selective opioid agonist [D-Ala(2), NMe(4), Gly-ol(5)]-enkephalin (DAMGO) in the VTA region was altered by pretreatment into the same site with equimolar doses of either GABA(A) (bicuculline) or GABA(B) (Saclofen) antagonists, and further, whether pretreatment with either general opioid or selective GABA receptor antagonists decreased feeding elicited by GABA(A) (muscimol) or GABA(B) (baclofen) agonists in the VTA region. DAMGO-induced feeding in the VTA region was dose-dependently decreased following pretreatment with either GABA(A) or GABA(B) antagonists in the absence of significant alterations in food intake by the antagonists per se. However, the presence of short-lived seizures following bicuculline in the VTA region suggests that this ingestive effect was caused by nonspecific actions. In contrast, GABA(B) receptors are involved in the full expression of mu-opioid agonist-induced feeding in this region since Saclofen failed to elicit either seizure activity or a conditioned taste aversion. Pretreatment with naltrexone in the VTA region reduced intake elicited by baclofen, but not muscimol. Finally, baclofen-induced feeding was significantly reduced by Saclofen, but not bicuculline, pretreatment in the VTA region. Therefore, possible coregulation between GABA(B) and opioid receptors in the VTA region, as suggested by immunocytochemical evidence, is supported by these behavioral effects upon ingestion.
David I B Kerr - One of the best experts on this subject based on the ideXlab platform.
-
3-amino-2-(4-chlorophenyl)-nitropropane is a new GABAB receptor agonist, more active peripherally.
European Journal of Pharmacology, 1993Co-Authors: David I B Kerr, Jennifer Ong, John Abbenante, David J. Doolette, Rh PragerAbstract:Abstract The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABAB receptors. N-BAC was less potent than baclofen as a GABAB receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC50s for baclofen = 4.1 ± 1.3 μM; N-BAC = 9.2 ± 0.3 μM) and vas deferens (IC50s for baclofen = 30 μM; N-BAC = 100 μM), competitively antagonished by phaclofen, 2-hydroxySaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA2 values for CGP 35348 with baclofen (4.7 ± 0.2) and N-BAC (4.6 ± 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABAB receptor agonist, N-BAC, is thus more active at peripheral than central GABAB receptors.
David J. Doolette - One of the best experts on this subject based on the ideXlab platform.
-
3-amino-2-(4-chlorophenyl)-nitropropane is a new GABAB receptor agonist, more active peripherally.
European Journal of Pharmacology, 1993Co-Authors: David I B Kerr, Jennifer Ong, John Abbenante, David J. Doolette, Rh PragerAbstract:Abstract The activity of the nitropropane analog of baclofen, 3-amino-2-(4-chlorophenyl)-nitropropane (N-BAC), has been examined at central and peripheral GABAB receptors. N-BAC was less potent than baclofen as a GABAB receptor agonist in depressing repetitive twitch contractions in the guinea-pig isolated ileum (IC50s for baclofen = 4.1 ± 1.3 μM; N-BAC = 9.2 ± 0.3 μM) and vas deferens (IC50s for baclofen = 30 μM; N-BAC = 100 μM), competitively antagonished by phaclofen, 2-hydroxySaclofen and CGP 35348 (3-aminopropyl-P-di-ethoxymethylphosphinic acid). In the ileum, the pA2 values for CGP 35348 with baclofen (4.7 ± 0.2) and N-BAC (4.6 ± 0.3) were not significantly different (P > 0.05), indicating that both agonists activate the same receptor type. By contrast, in rat neocortical slices, N-BAC was 20 times weaker than baclofen in attenuating spontaneous discharges, sensitive to CGP 35348, whilst it was 100 times less potent than baclofen in depressing evoked CA1 population spikes in the hippocampus. This new GABAB receptor agonist, N-BAC, is thus more active at peripheral than central GABAB receptors.
